In the past, attempts have been made to trigger the immune system to mount an efficient response against malignant cells. Despite significant and promising progress, such a response has yet to be fully attained and many immune based therapies have proved disappointing.
Numerous studies using in vitro cellular assays demonstrate that cytotoxic lymphocytes have the ability to kill tumour cells. Why this immune based destruction does not effectively control tumour growth in vivo is a conundrum. The cancer patient also has increased concentration of circulating immune complexes, indicating the immune system is active, particularly against certain tumour antigens. The level of these immune complexes can increase with disease progression (Horvath et al, 1982; Aziz et al, 1998).
Regulatory cells (also referred to in the art as suppressor cells) have been implicated in a subjects immune response to cancer (North and Awwad, 1990; WO 03/068257). As most cancer antigens are actually produced by the patient they are considered as “self” by the immune system. Upon the presence, and/or increased quantity, of tumour antigen the hosts immune system mounts a response characterized by the production of effector cells which target cells producing the tumour antigen. However, in many instances these effector cells are recognized by the immune system as targeting the hosts own cells, and hence a population of regulator cells are produced to down-regulate the effector cell population. Thus, the production of these regulator cells limits the ability of the immune system to effectively remove cancer cells.
More recently, regulator cells have been shown to be involved in a subjects immune response to a viral infection. WO 02/13828 describes the production of regulator cells during retroviral infection, and methods of treating such infections by down-regulating the regulator cell population whilst maintaining the effector cell population. Furthermore, Peterson et al (2002) observed that a population of CD4+ regulator cells were suppressing the ability of CD8+ effector cells to control Friend murine retrovirus infections in mice.
Measurements of certain acute-phase protein plasma concentrations can be of diagnostic or prognostic value under specific clinical conditions. The best known acute-phase protein is C-reactive protein (CRP). CRP is a plasma protein that rises in the blood with the inflammation from certain conditions. The level of CRP in blood plasma can rise as high as 1000-fold with inflammation. Conditions that commonly lead to marked changes in CRP include bacterial and viral infection, trauma, surgery, burns, inflammatory conditions, coronary and vascular disease and advanced cancer.
Most acute phase proteins are synthesized by hepatocytes, some are produced by other cell types, including monocytes, endothelial cells, fibroblasts and adipocytes. Acute phase proteins include serum amyloid A (SAA), CRP and serum amyloid P component (SAP).
The immediate responsiveness of CRP and SAA to stimuli, together with their wide concentration range and ease of automated measurement, have led to plasma CRP and SAA levels being used to monitor accurately the severity of inflammation and the efficacy of disease management during certain disease conditions.
WO 03/070270 describes the use of acute phase inflammatory markers in regimes for the effective treatment of HIV. These methods rely on at least partially “resetting” the immune system by a treatment such as HAART followed by the analysis of acute phase inflammatory proteins as markers for effector/regulator cell expansion. The emergence of acute phase inflammatory proteins appears to be linked to effector cell expansion, which occurs before regulator cell expansion, and thus the patient can be treated with a suitable agent which allows the effector cell population to be maintained whilst destroying, preventing the production of, or reducing the activity of, regulator cells. In essence, upon withdrawal of HAART treatment it was considered that the patient s immune system would treat the re-emerging HIV particles as a new infection, and hence a new population of effector cells would be produced.
Similar to WO 03/070270, WO 03/068257 relates to at least partially resetting the immune system, however, in this instance in the context of the treatment of cancer. Again, the treatment is focussed on the initial re-emergence of effector cells following a reduction in tumour load through techniques such as surgery or the administration of anti-proliferative drugs.
Neither WO 02/13828, WO 03/070270 or WO 03/068257 appreciate that the immune response is cycling in a cancer or HIV patient regardless of the administration of treatment for these diseases. The present invention is based on the realization of this cycling, and thus provides methods for the treatment of diseases linked to regulator cell production or activity.